HD Insights™

H D I N S I G H T S HD Insights, Vol. 10 12 Copyright © Huntington Study Group 2015. All rights reserved. H D I N S I G H T S Cicchetti, cont... CICCHETTI: I do not know of any studies that have specifically monitored the changes in these markers following treatment. However, one study has demonstrated normalization of cytokine levels and moderate motor benefits in animal models of the disease using a bone marrow transplant paradigm 7 and a recent publication in Brain has reported that glucan-encapsulated siRNA can significantly reduce HTT levels in monocytes and macrophages derived from pre-manifest HD patients, which in turn decreases the levels of pro-inflammatory cytokines released by these cells. 8 There were also a number of studies reporting benefits of the anti-inflammatory drug minocycline in animal models of HD, but the treatment did not translate into meaningful improvements in HD patients. 9 HD INSIGHTS: So we could be looking at mHTT and peripheral monocytes to determine whether new therapies are efficacious in HD? CICCHETTI: If we establish that inflammation or immunity indeed plays a critical role in HD, we could certainly use some of these cell populations to monitor treatment efficacy. But even though inflammation/immunity may be important in driving disease pathology, I suspect the problem is much more complex, and we are likely to need to treat the disease with a combination of approaches. Gene-silencing therapies using antisense oligonucleotides (ASOs) 10 or RNA interference targeting specific SNPs to lower mHTT 11,12 seem very promising in animal models of the disease. These methodologies would not target propagation per se but attack the problem upstream of propagation, aiming at the mHTT mRNA before the gene is translated. However, in anticipated clinical trials, ASOs will be delivered through the cerebrospinal fluid and siRNA directly into the brain to target cerebral mHTT, not the expression of mHTT in the periphery. I assume the delivery of ASOs could eventually be considered via the peripheral system to target peripheral cells. HD INSIGHTS: And you think these peripheral monocytes could be used as an assay of the efficacy of these interventions? CICCHETTI: They could be, or any other blood-borne cells. The monocytes are very few compared to other types of blood cells. We cannot discard other populations as potential biomarkers, nor the microvesicles and exosomes that they can release. HD INSIGHTS: You mentioned that your research has implications for targets for therapy. Could you elaborate? CICCHETTI: Of the mechanisms that we proposed or suspect underlie mHTT propagation, there are two that we are most eager to investigate. The first is trans-synaptic spread through the corticostriatal pathway, for which there is accumulating evidence both in vitro and in vivo, especially with the latest paper published by Pecho-Vrieseling et al. in Nature Neuroscience. 13 The work of Dr. William Yang showing that modulating the expression of mHTT through the corticostriatal pathway can actually change some characteristics of the pathology, also provides evidence for the importance of this pathway in non – cell-autonomous mechanisms of protein spread. 14 Gene silencing methodologies, either ASOs or siRNAs, applied directly into the brain could block the propagation of the mutant protein. The second possibility for therapeutic development would be to target circulating immune cells, which we hypothesize carry the mutant protein and can transmigrate into the brain via leaky blood vessels. Of course, there may be other explanations for the presence of mHTT within genetically unrelated grafted tissue. Explanations could be oxidative stress, inflammation, or poor trophic support. But again, I think that mHTT propagations via the corticostriatal pathway and/or the immune system are the most likely scenarios and therefore the best therapeutic targets. HD INSIGHTS: Do you see any therapies that are currently under development that could potentially address either one of these possibilities? CICCHETTI: To target the immune system, we could consider vaccines, but this approach has not yielded any benefits in other diseases such as Alzheimer disease, and in fact generates a number of complications. Intrabodies, which are recombinant single- chain antibody fragments, have shown significant effects in reducing the striatal mHTT protein load. 15 ASOs are also showing great promise in animal studies, and could be used to target both cerebral and peripheral mHTT. 10 No matter what the approach, it will be critical to select specific populations of HD patients, before excessive neuropathology has set in. Selecting late-stage patients will prove more difficult because there will be much more aggregated forms of mHTT in such patients, whom will not respond as well to ASOs. We need to silence the gene early, given that the soluble protein is likely to be the toxic form, not the aggregate itself. HD INSIGHTS: Your paper has created quite a buzz, and was recently recognized as one of the papers of the year by the Editorial Board of HD Insights. Can you tell us who funded the study? CICCHETTI: No one. But since the publication of the manuscript, we have received all the funding we have applied for. Persistence paid off and I am counting my blessings! (continued on Page 13...)

• Cover